BACKGROUND　Gastric　adenocarcinoma　with　primitive　phenotypes　has　recently　attracted　increasing　attention　due　to　its　aggressive　nature　and　challenging　diagnosis.　Gastric　adenocarcinoma　with　enteroblastic　differentiation　(GAED)　and　hepatoid　adenocarcinoma　(HAC)　were　previously　regarded　as　gastric　adenocarcinoma　with　primitive　enterocyte　phenotype　(GAPEP).　GAPEP　is　known　for　its　poor　prognosis,　and　the　accurate　diagnosis　of　GAPEP　directly　affects　therapeutic　decision-making.　Despite　their　poor　prognosis　and　morphological　heterogeneity,　the　molecular　drivers　of　GAPEP,　particularly　methylation-driven　mechanisms,　remain　poorly　explored.　AIM　To　investigate　the　clinicopathological　and　molecular　characteristics　of　GAPEP　and　establish　an　integrative　diagnostic　strategy　to　guide　therapeutic　decision-making.　METHODS　Based　on　the　expression　profile　and　morphology,　patients　were　divided　into　three　groups:　GAPEP　(including　GAED　and　HAC),　conventional　gastric　cancer　(CGC),　and　CGC　expressing　primitive　phenotypic　markers.　We　analyzed　clinicopathological　features　and　overall　survival.　Data　from　The　Cancer　Genome　Atlas　were　also　analyzed,　and　functional　enrichment　analysis　was　conducted.　RESULTS　GAPEP　showed　diverse　morphology,　and　immunohistochemical　staining　alone　was　not　adequate　for　accurate　diagnosis.　Histologically,　GAPEP　was　characterized　by　large,　polygonal　tumor　cells　with　supranuclear　or　subnuclear　vacuoles,　a　＂piano　keyboard-like＂　appearance,　and　clear　or　eosinophilic　cytoplasms.　Compared　to　CGC　and　CGC　expressing　primitive　phenotypic　markers,　GAPEP　displayed　more　aggressive　clinical　features.　Molecular　analysis　showed　significant　differences　in　molecular　subtypes,　TP53　mutation,　ERBB2　amplification,　ARID1A　mutation,　MSI　status,　and　CpG　island　methylator　phenotype　category.　Genomic　analysis　revealed　that　TP53　mutations,　APC　mutations,　and　ERBB2　amplifications　were　more　frequent　in　GAPEP.　Genes　involved　in　methylation　processes　were　highly　upregulated　in　GAPEP.　HAC　and　GAED　shared　similar　clinicopathological　and　genetic　characteristics.　Functional　enrichment　analysis　highlighted　the　critical　role　of　methylation　in　the　development　of　GAPEP.　CONCLUSION　The　diversity　and　aggressiveness　of　GAPEP　are　driven　by　deregulated　methylation,　necessitating　the　integration　of　morphological　and　immunohistochemical　diagnosis.　Targeting　methylation　can　provide　new　therapeutic　opportunities　for　treating　this　aggressive　cancer.